Benign prostatic hyperplasia (BPH) and associated Lower Urinary Tract Symptoms (LUTS) are a major public health problem with high morbidity and associated costs. At present, BPH patients are treated fairly uniformly. However, a true understanding of the disease process and the role of comorbidities in driving progression should allow stratification of patients into sub-groups and a more personalized approach to therapy, leading to better efficacy and lower rates of surgical intervention. We have recently developed a human BPH tissue repository composed of samples of incidental BPH found at prostatectomy and of tissue from patients whose BPH had progressed to surgical intervention. We also investigated how mouse models of diabetes and obesity reflect specific aspects of human BPH. This provides new tools to address questions relating to specific components of human BPH and to correlate murine responses to human samples. Two key observations have emerged in our recent studies. First, gene expression changes in the progression from incidental BPH to symptomatically severe, medically-refractory disease showed a pattern that mirrored changes seen in a number of chronic inflammatory conditions such as psoriasis, arthritis and inflammatory bowel disease. These changes prominently included basal cell expression of AP-1 factors, notably c-FOS, which were associated with disease progression to surgery and also with resistance to 5ARI therapy. Second, we determined that obese (Ob/Ob) and non-obese diabetic (NOD) mice show distinct features of prostatic enlargement and inflammation that mirror aspects of human BPH. The purpose of the proposed work is to define the role of AP-1 stress responses in prostatic hyperplasia and to determine whether drug regimens that affect such pathways alter the progression of prostatic hyperplasia. To address these ideas three Specific Aims are proposed. Specific Aim 1. Determine whether specific systemic stressors affect AP-1 signaling and prostate histopathology. This aim tests the hypothesis that diabetes, obesity and inflammation will give rise to distinct patterns of AP-1 factor activation and associated growth in the mouse prostate and that these changes will be reflected in human samples. Specific Aim 2. Determine whether tissue-specific AP-1 factors drive inflammation, prostatic hyperplasia and resistance to therapy. This aim tests the hypothesis that prostatic hyperplasia can be rendered resistant to androgen ablation by AP-1 factor activation secondary to diabetes, obesity or inflammation. Specific Aim 3. Determine whether reversing obesity, diabetes or inflammation reduces prostatic hyperplasia. This aim tests the hypothesis that reducing AP-1 activity by reversing obesity, diabetes or inflammation will reduce hyperplasia and restore sensitivity to therapy.